Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer’s disease etiopathogenesis

Laura Madrid, Sonia Moreno-Grau, Shahzad Ahmad, Antonio González-Pérez, Itziar de Rojas, Rui Xia, Pamela V.Martino Adami, Pablo García-González, Luca Kleineidam, Qiong Yang, Vincent Damotte, Joshua C. Bisl, Fuensanta Noguera-Perea, Céline Bellenguez, Xueqiu Jian, Juan Marín-Muñoz, Benjamin Grenier-Boley, Adela Orellana, M. Arfan Ikram, Philippe AmouyeClaudia L. Satizabal, Luis Miguel Real, Carmen Antúnez-Almagro, Anita DeStefano, Alfredo Cabrera-Socorro, Rebecca Sims, Cornelia M.Van Duijn, Eric Boerwinkle, Alfredo Ramírez, Myriam Fornage, Jean Charles Lambert, Julie Williams, Sudha Seshadri, Janina S. Ried, Agustín Ruiz, Maria Eugenia Saez

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analyzed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterized a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.

Original languageEnglish (US)
Pages (from-to)9277-9329
Number of pages53
JournalAging
Volume13
Issue number7
DOIs
StatePublished - Apr 15 2021

Keywords

  • APOE
  • Alzheimer’s disease
  • biomarkers
  • integrative analysis

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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